# US 9,040,560 B2 · Amino azaheterocyclic carboxamides

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- Number: US 9,040,560 B2
- Document ID: US9040560B2
- Status: Granted
- Kind: B2
- Application number: 14/105,974
- Filed: 2013-12-13
- Published: 2014-04-17
- Granted: 2015-05-26
- Earliest claimed: 2009-02-11
- Assignees: Merck Patent GmbH
- Applicants: Merck Patent GmbH
- Inventors: Amanda E. Sutton; Thomas E. Richardson; Bayard R. Huck; Srinivasa R. Karra; Xiaoling Chen; Yufang Xiao; Andreas Goutopoulos; Ruoxi Lan; David Perrey; Harold George Vandeveer; Lesley Liu-Bujalski; Frank Stieber; Brian L. Hodous; Hui Qiu; Reinaldo C. Jones; Brian H. Heasley
- Web page: https://patentgrep.com/patent/US9040560B2

## CPC

- C07D 215/04: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- A61K 31/47: Quinolines; Isoquinolines
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/94: Nitrogen atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides novel substituted amino azaheterocyclic carboxamide compounds according to Formula (I), their manufacture and use for the treatment of hyperproliferative diseases, such as cancer.

## Claims

### Claim 1

A compound of Formula (I):
and pharmaceutically acceptable salts thereof,
wherein:
X is C—R3,
Y is NH,
R1 is L1-R4-L2-R5-L3-R6, L1-R4-L2-R5 or L1-R4,
R2′, R2″ each, independently of one another, are H, A, Hal, OH, OA, SH, CN, NH2, NO2, NHA, NH-L1-Ar, NHCOA, NHCO-L1-Ar, NHSO2A, NHSO2-L1-Ar, NHCONHA or NHCONH-L1-Ar, L1-Ar, O-L1-Ar, L1-R4,
L1, L3 each, independently of one another, are a single bond, unbranched or branched alkylene having 1, 2, 3, 4 or 5 C atoms, which may be unsubstituted or mono- or disubstituted with Hal, OH, CN, NH2, NH(LA), N(LA)2, NO2, COOH, N3, ethenyl or ethynyl, and/or monosubstituted with R4,
R3 is H, A, Hal, OH, COOH, SH, NH2, NO2 or CN,
R4, R5, R6 each, independently of one another, are Ar, or monocyclic alkyl having 3, 4, 5, 6 or 7 ring atoms, in which one or two CH2 groups may be replaced by an O or S atom and/or by an —NH—, —NA-, —CHA-, —CO—, —CH═N— or —CH═CH— group, and/or in which the connecting CH group may be replaced by an N atom, and which may be mono- or disubstituted by Hal or LA,
L2 is —NHCO—, —NHCOO—, —NHCONH—, —NHCONA-, —NHCOA-, —O—, —S—, —NH—, —NHSO2—, —SO2NH—, —CONH—, —CONHCONH—, —NHCONHCO—, or -A-,
Ar is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N, O and/or S atoms and 5, 6, 7, 8, 9, or 10 skeleton atoms, which may be unsubstituted or, independently of one another, mono-, di- or trisubstituted by Hal, A, OH, SH, OA, NH2, NHA, NA2, NO2, CN, OCN, SCN, COOH, COOA, CONH2, CONHA, CONA2, NHCOA, NHCONHA, NHCONH2, NHSO2A, CHO, COA, SO2NH2, SO2A and/or SO2Hal, and in which a ring N-atom may be substituted by an O-atom to form an N-oxide group, and in which in the case of a bicyclic aromatic cycle on of the two rings may be partly saturated,
A is unbranched or branched linear or cyclic alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH2 groups may be replaced by an O or S atom and/or by an —NH—, —CO—, —NHCOO—, —NHCONH—, —N(LA)-, —CONH—, —NHCO— or —CH═CH— group, and in which 1-3 H atoms may be replaced by Hal, and in which one or two CH3 groups may be replaced by OH, SH, NH2, NH(LA), N(LA)2, NHCOOH, NHCONH2 or CN,
LA is unbranched or branched, linear alkyl having 1, 2, 3 or 4 C atoms, and
Hal is F, Cl, Br or I.

### Claim 2 (depends on 1)

The compound of claim 1, of Formula (II):
and pharmaceutically acceptable salts thereof,
wherein R2 is H, A, Hal, OH, OA, SH, CN, NH2, NO2, NHA, NH-L1-Ar, NHCOA, NHCO-L1-Ar, NHSO2A, NHSO2-L1-Ar, NHCONHA or NHCONH-L1-Ar, L1-Ar, O-L1Ar, or L1-R4.

### Claim 3 (depends on 1)

The compound of claim 1, of Formula (III):
and pharmaceutically acceptable salts thereof,
wherein R2 is H, A, Hal, OH, OA, SH, CN, NH2, NO2, NHA, NH-L1-Ar, NHCOA, NHCO-L1-Ar, NHSO2A, NHSO2-L1-Ar, NHCONHA or NHCONH-L1-Ar, L1-Ar, O-L1-Ar, or L1-R4.

### Claim 4 (depends on 1)

The compound of claim 1, wherein:
in Subformula 1
X is C—R3,
Y is NH,
R3 is H,
in Subformula 3
X is C—R3,
Y is NH,
R3 is H,
R1 is L1-R4,
R2′, R2″ are H,
L1 is methylene, or
in Subformula 39
X is CH,
Y is NH,
R1 is L1-R4,
L1 is methylene which is substituted with aminomethyl, (methyl-amino)methyl, (dimethyl-amino)methyl or 2-aminoprop-2-yl,
R4 is phenyl which is unsubstituted or substituted as defined for Ar in claim 1,
R2 is H, methoxy, methyl, ethyl, hydroxymethyl, methoxymethyl or cyano,
and pharmaceutically acceptable salts thereof.

### Claim 5 (depends on 1)

The compound of claim 1, wherein:
in Subformula 3
X is C—R3,
Y is NH,
R3 is H,
R1 is L1-R4,
R2′, R2″ are H,
L1 is methylene,
in Subformula 39
X is CH,
Y is NH,
R1 is L1-R4,
L1 is methylene which is substituted with aminomethyl, (methyl-amino)methyl, (dimethyl-amino)methyl or 2-aminoprop-2-yl,
R4 is phenyl which is unsubstituted or substituted as defined for Ar in claim 1,
R2 is H, methoxy, methyl, ethyl, hydroxymethyl, methoxymethyl or cyano,
and pharmaceutically acceptable salts thereof.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound is:
4-((S)-2-Amino-1-phenyl-ethylamino)-quinoline-8-carboxylic acid amide, and pharmaceutically aceptable salts thereof.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising: i) a compound according to claim 1 or a pharmaceutically acceptable salt thereof, as active ingredient and ii) a pharmaceutically acceptable carrier.

### Claim 8 (depends on 1)

A kit consisting of separate packs of:
(i) an effective amount of a compound of claim 1 and,
(ii) an effective amount of an additional medicament active ingredient.

### Claim 9

A process for the manufacture of a compound of Formula (I), comprising: i) reacting a carboxylic acid compound of Formula (I-III)
with LA-OH to the corresponding carboxylic LA ester of Formula (I-II),
ii) reacting said carboxylic LA ester of Formula (I-II) with H2N—R1 to yield a compound of Formula (I-I),
and iii) further reacting said compound of Formula (I-I) under conditions such that said compound of Formula (I-I) is converted into the carboxylic amide of Formula I